1. Technical Field
This invention relates to prognostic methods for use in predicting the likelihood that a normal or hyperplastic mammary cell will progress to neoplasia. The methods enable oncologists to determine the degree of aggressiveness to be employed in treatment of breast cancer and benign, hyperplastic, breast conditions.
2. Background
Breast cancer is one of the most common cancers and is the third leading cause of death from cancers in the United States with an annual incidence of about 182,000 new cases and nearly 50,000 deaths. In the industrial world, approximately one in eight women can expect to develop breast cancer in her lifetime. The mortality rate for breast cancer has remained unchanged since 1930. It has increased an average of 0.2% per year, but decreased in women under 65 years of age by an average of 0.3% per year. Preliminary data suggest that breast cancer mortality is beginning to decrease, probably as a result of an increase in the diagnosis of localized cancer and carcinoma in situ. For review, see, Marchant (1994) Contemporary Management of Breast Disease II: Breast Cancer, in: Obstetrics and Gynecology Clinics of North America 21:555-560; and Colditz (1993) Cancer Suppl. 71:1480-1489.
Although the etiology of breast cancer has not been elucidated, it is hypothesized to evolve from normal epithelium through certain nonmalignant proliferative diseases to carcinoma in situ, either ductal or lobule, to primary invasive cancer and finally, to metastatic cancer. At some point in the progression from normal tissue to malignancy, tumor initiation occurs. Tumor initiation and the early stages of progression, do not necessarily render a cell malignant, in fact, the cell may appear histologically normal. To date, there has been no method of detecting mammary cells which have undergone tumor initiation but which are not yet neoplastic.
The earliest and most favorable form of breast carcinoma capable of being recognized is the intraepithelial, or noninvasive, stage. Its early detection has been greatly increased by mammography. In situ carcinoma is characterized by a malignant transformation of the epithelial cells that line the breast lobules and major lactiferous ducts but without invasion of these malignant cells beyond the investing basement membrane into the surrounding stroma. For review, see Frykberg et al. (1994) W. J. Surg. 18:45-57.
Several genetic markers have been associated with breast cancer. A particular mutation in one of these, BRCA1, has recently been found to be associated with a specific ethnic group, Ashkenazi Jews, which has a particularly high incidence of breast cancer. A number of other tumor markers are associated with breast cancer, such as myc, p53, erbB2, bek, and flg. Adnane et al. (1991) Oncogene 6:659-661. The erbB2 gene (also known as HER-2/neu) encodes a 185 kDa membrane growth factor homologous to the epidermal growth factor receptor. The erbB2 gene is amplified in 61 of 283 tumors (22%) tested in a recent survey. Adnane et al. (1991).
Although original therapy for breast cancer was restricted to radical mastectomy, more conservative, breast-preserving, surgeries are now often available. Also, a wide variety of adjuvant therapies are now available including hormonal, radiation and chemotherapeutics. For review, see Posner et al. (1995) Int. Surg. 79:43-47. The availability of less radical treatment regimens necessitates methods of identifying patients who are destined to develop tumor recurrence. Although several promising prognostic factors have been identified, such as DNA ploidy, S-phase analysis, Cathepsin D, erbB2 oncogene expression and epidermal growth factor expression, designing treatment regimens based on these factors is thought to be xe2x80x9cimmature.xe2x80x9d Posner et al. (1995).
Another marker of cancer, particularly invasive breast cancer, is loss of heterozygosity (LOH). For review, see O""Connell (1994) Breast Cancer Res. Treat. 32:5-12. A particular LOH has been shown to be positively correlated with the change from in situ to invasive behavior. Stratton et al. (1995) J. Pathol. 175:195-201. In breast cancer, LOH has been shown at a variety of alleles. A high incidence of LOH has been found at chromosome 11q23 in non-familial breast cancers in situ, invasive and metastatic tumor cells. Koreth et al. (1995). J. Pathol. 176:11-18; and Tomlinson et al. (1995) J. Clin. Pathol. 48:424-428. LOH has been found, on chromosome 11q13 in 67% of microdissected invasive breast cancer and in a subpopulation of the in situ carcinomas of the invasive breast cancer. Zhuang et al. (1995) Cancer Res. 55:467-471. LOH has been found on chromosome 16q in intracystic papillary carcinomas in breast cancer and is thought to be involved in acquisition of malignant phenotype. Tsuda et al. (1994) Jpn. J. Cancer Res. 85:992-996. LOH has also been detected on two separate regions on chromosome 3p in breast cancers; 3p13-14 and 3p24-26. Chen et al. (1994) Cancer Res. 54:3021-3024.
There is circumstantial evidence in the literature that some breast cancers may result from multiple pathways within a localized region of the breast. Recently, invasive cancers and associated preinvasive and premalignant components such as ductal carcinoma in situ (DCIS) and atypical hyperplasia were examined for LOH at various autosomal loci. There were some cases which showed patterns of LOH consistent with the conclusion that the premalignant and invasive components resulted from two independent pathways of malignant progression. O""Connell et al. (1994)
LOH has also been found in a wide variety of tumors. In only one instance has a particular LOH, 3p21.3, been found in a tumor, non-small cell lung carcinoma, and in normal, adjacent, tissue. Siegfried et al. (1995) Proc. Am. Assoc. Cancer Res. 36:545 (Abstract, 3247).
All references cited herein, both supra and infra, are hereby incorporated herein by reference.
The present invention encompasses methods for determining the likelihood of benign hyperplastic breast tissue or normal breast tissue adjacent to carcinoma tissue will become malignant. The methods comprise substantially isolating the tissue; and determining the presence of loss of heterozygosity (LOH) at chromosome 3p24. LOH at chromosome 3p24 is a prognostic indicator that the tissue is likely to become malignant.